Diffuse Hyperintensity Signals and Neurodegerative Diseases

Diffuse hyperintensity signals in the brain are seen in many conditions due to various causes from infections to aging and certain types of cancer. It takes an astute radiologist to know the difference.

As discussed elsewhere on this website, hyperintensity signals are one of the hallmark signs of multiple sclerosis due to demyelination. What makes MS lesions unique compared to the diffuse hyperintensity type is where they tend to show up in the brain.

The primary difference is that MS lesions aren't diffuse. Instead, they tend to show up above the covering over the cerebellum, called the tentorium cerebelli. The cerebellum is located in the posterior fossa. Consequently, their location above the tentorium cerebelli is referred to as supratentorial.MS lesions also tend to be located around the cavities in the middle of the brain, called ventricles, which contain cerebro-spinal fluid (CSF). For this reason they are technically called periventricular lesions. MS lesions further have a tendency to be located around the largest veins in the brain so they are also referred to as perivenular. In brief, in contrast to diffuse hyperintensity signals, hyperintensity signals associated with MS lesions tend to be found in specific locations that are supratentorial, periventricular and perivenular.

Many researchers have attempted to find a cause and explanation for the peculiar location of the supratentorial, periventricular and perivenular MS lesions. Probably the best explanation so far is venous back jets as proposed by Dr. Franz Schelling an Austrian physician and one of the leading experts in the world on the subject of MS. Venous back jets and MS hyperintensity signal lesions are discussed elswhere on this site.

As far as neurodegenerative diseases are concerned, diffuse hyperintensity signals have been associated with Alzheimer’s disease and Parkinson’s disease. Moreover, in addition to Alzheimer's disease, diffuse hyperintensity signals are also associated with Binswanger’s disease, which is also know as multi-infarct dementia. The brain scan below is of a case with multi-infarct dementia. The white spots are abnormal hyperintensity signals close to the lateral ventricles, which are the cavities in the brain scan shaped like a white letter H. The periventricular area of the lateral ventricles is a fairly common site to find hyperintensity signals in many conditions. In this case the hyperintensity signals are also scattered throughout the brain far from the lateral ventricles.

Note: the brain scan below was copied with permission from an educational website for radiologists called Radiopaedia.org. This particular scan comes from a collection of cases contributed by Dr. Frank Galliard, the current editor.

Similar hyperintensity signals are seen in vascular dementia. Both multi-infarct dementia and vascular dementia are close cousins to Alzheimer‘s so the signs and symptoms are similar. They are so close that some researchers have begun to suspect that they may have similar causes.
When it comes to Parkinson's disease, researchers have associated diffuse hyperintensity signals with a condition called multisystem atrophy (MSA), which is sometimes called Shy-Drager syndrome depending on differences in signs and symptoms. For instance, in MSA there is a predominance of symptoms similar to Parkinson's. Shy-Drager, on the other hand, has a preponderance of autonomic symptoms, which I will cover elsewhere as this site develops. Similar hyperintensity signals are also seen in vascular Parkinson’s disease. Both of these conditions have similar signs and symptoms to Parkinson’s disease but they don‘t respond to the drug levodopa (dopamine) as do classic cases of Parkinson‘s.

In addition to the variant vascular forms of Alzheimer's and Parkinson's diseases, diffuse hyperintensity signals have also been associated with a condition called diffuse axonal injury (DAI). DAI is typically associated with traumatic brain injuries such as concussions from falls and assaults, motor vehicle accidents, and shaken baby syndromes. If you look closely at the brain scan below, the image on the right shows axonal injuries that appear as small black spots in the right hemisphere of the brain. The image on the left shows white spots in the same area. The images are simply reversed like negatives for black and white photos; that is, the black and white shades are reversed. Reversing the image makes it easier for radiologists to identify the lesions and determine what they are, which isn't always clear.

Diffuse hyperintensity signals seen in diffuse axonal injuries are believed to be caused by damage to the sheath that surrounds the axons of nerve cells called the axolemma. The axon is an appendage on the nerve cell body that carries the signal from the nerve cell to a target destination such as another nerve or a muscle for example.

The picture below is of a nerve cell. The axolemma sheath that surrounds the axon (brown) is shown in blue. The axolemma sheath is actually a separate cell that makes myelin. In the brain and cord the cells that make the myelin sheaths that surround the axons are called oligodendrocytes. Outside the brain and cord, in the rest of the body the axolemma sheaths are formed by Schwann cells. In either case, the myelin is made of fat layers with protein sandwiched in between to give it strength. The axolemma myelin sheath acts like an insulator around a bare wire, it is interrupted periodically by nodes (breaks in the blue) where the nerve is exposed. The design allows nerve signals to jump between nodes, which speeds conduction. Bundles of axons make up the white matter in the brain.

Sudden acceleration of the head and neck followed by rapid deceleration causes shear stresses in the brain as tissues of different strengths and densities attempt to slide against one another. For example, the different lobes and parts of the brain slide against each other, as well as the connective tissues of the cranial vault that separate the vault into compartments. Whiplash type forces also cause axons to slide inside their axolemma sheaths. Violent shear forces can overstretch this delicate interface between the axons and their axolemma sheaths thus causing them to tear, snap and break.

Other researchers, however, believe the damage is caused by damage to the inner structure of nerve cells that eventually causes the myelin to breakdown. They maintain that structural changes in the cell walls adversely change the flow of chemicals and elements across the cell wall that eventually cause it to malfunction and die. It could very well be one or the other and sometimes both.

Regardless of the cellular causes of demyelination, diffuse hyperintensity signals due to axonal injuries tend to show up in areas of the brain where the surfaces of tissues of different strengths and densities interface, causing them to move against each other at different speeds. This causes shear stress. The distance of the tissue from the source of the trauma also affects the outcome. Typically, DAI was associated with severe traumatic brain injuries and permanent states of vegetative coma. Evidence shows, however, that even mild to moderate head injuries can cause diffuse axonal injuries. Some researchers now suggest that there are different degrees of diffuse axonal injury ranging from mild to severe.

Interestingly, many years ago when I started my investigation, researchers suggested that chronic edema could damage myelin similarly simply by overstretching it. In this case, however, in contrast to sudden whiplash type trauma causing diffuse axonal injury, the overstretching occurs slowly over time. Furthermore, in this regard, Alzheimer’s disease is sometimes associated with normal pressure hydrocephalus (NPH) and enlargement of the lateral ventricles (ventriculomegaly).

The corpus callosum forms the roof of the lateral ventricles. The corpus callosum connects the left and right hemispheres of the brain. It is the largest myelinated structure in the brain. In addition, and interesting to note, periventricular hyperintensity signals are often seen in the corpus callosum and periventricular areas in Alzheimer’s disease. In this regard, NPH may be the cause as it stretches the lateral ventricles and corpus callosum. Chronic edema may also similarly stretch different areas depending on tissue densities and strength to resist deformation resulting in diffuse axonal myelin injuries.

Researchers also theorize that diffuse hyperintensity signals due to axonal injuries cause changes in the typical element and chemical transport system that occurs across the affected myelinated axon walls. These results in faulty signal conduction and faulty cell chemistry. The changes in conduction and chemistry cause damage over time so that diffuse axonal injuries are also associated with delayed onset in signs and symptoms, which can show up long after the trauma.

In addition to pressure from shear stress or chronic NPH, diffuse hyperintensity signals are also seen in mini strokes and migraine headaches. Both are associated with arterial blood flow problems that can result in chronic ischemia (decreased arterial blood flow) to the brain.

But that’s an entirely different story I will discuss as this site develops. Suffice it to say that both may be associated with delayed onset as well.